A patent review of BRD4 inhibitors (2013-2019)

ABSTRACT

Introduction: The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, functions as an ‘epigenetic reader’ that binds to acetylated lysine (KAc) residues on histone tails sophisticatedly regulating chromatin structure and gene expression. Recently, emerging evidence demonstrates that BRD4 plays a significant role in the occurrence and progression of several malignant human diseases especially cancers, making it a hot target in cancer therapy.

Areas covered: This review mainly summarizes the patents of BRD4 inhibitors that have been authorized from 2013 to 2019. The patents are mostly described in terms of chemical structures, molecular mechanisms of action, pharmacological activities and potential clinical applications, including combination therapies. The development of BRD4 inhibitors in the clinical phase has been highlighted. Prospects for further development of more selective BRD4 inhibitors are provided.

Expert opinion: In 2013–2019, several previously known chemical scaffolds have been further developed and disclosed. Although many small molecule BRD4 inhibitors with high potency and diverse scaffolds have been developed, the selectivity of most BRD4 inhibitors still needs to be improved. Therefore, the development of more selective small molecule inhibitors or combined use of drugs such as immunotherapy may provide new ideas for drug development.

KEYWORDS:

• Bromodomain-containing protein 4 (BRD4)
• bromodomain and extra-terminal (BET) family
• small molecule inhibitors
• cancer
• patent
• therapeutic potential

Article highlights

• As a potential target for cancer treatment, the bromodomain-containing protein 4 (BRD4) has received extensive attention in both academia and industry in recent years. Currently, more than 20 BRD4 inhibitors have entered clinical trials for the treatment of hematologic malignancies, solid tumors, and other diseases.

• In this review, patented BRD4 inhibitors BRD4 (2013–2019) were collected, classified according to their chemical structures, and their representative compound was described with reported biological activities, as well as the potential clinical applications.

• Deep exploration of the mechanism of action of BRD4(2) selective inhibitors ABBV-075, ABBV-774 and GSK340 is helpful to further clearly investigate the pathological role of each single bromodomain and explore the therapeutic efficacy of domain-selective BRD4 inhibitors.

The development of dual BRD4 and kinase inhibitors is expected to enhance the therapeutic response for the treatment of a variety of tumors.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (81625022, 91853205, 81821005 to C Luo.); the National Science and Technology Major Project (2018ZX09711002 to C Luo); the K. C. Wong Education Foundation to C Luo and the Chinese Academy of Sciences (XDA12020353 and XDA12050401 to C Luo).